Systems and methods for applying a selected treatment agent into contact with tissue to treat disorders of the gastrointestinal tract

ABSTRACT

Systems and methods that treat disorders of the gastrointestinal tract by applying one or more treatment agents to tissue at or near the region where abnormal neurological symptoms or abnormal tissue conditions exist. The treatment agent is selected to either disrupt the abnormal nerve pathways and/or to alleviate the abnormal tissue conditions. The treatment agent can include at least one cytokine and/or at least one vanilloid compound to evoke a desired tissue response. The systems and methods can be used a primary treatment modality, or as a neoadjuvent or adjuvant treatment modality.

RELATED APPLICATIONS

[0001] This application is a continuation-in-part of co-pending U.S.patent application Ser. No. 09/304,737, filed May 4, 1999 and entitled“Systems and Methods for Treating the Cardia of the Stomach andAdjoining Tissue Regions in the Esophagus.”

FIELD OF THE INVENTION

[0002] In a general sense, the invention is directed to systems andmethods for treating interior tissue regions of the body. Morespecifically, the invention is directed to systems and methods fortreating dysfunctions of organs and tissue in the gastrointestinaltract.

BACKGROUND OF THE INVENTION

[0003] Disorders of organs or tissue of the gastrointestinal tract canbe caused by as neurological factors (such as abnormal nerve impulses)or by physical factors (such as excess tissue volume).

[0004] For example, intestinal motility (i.e., the contraction ofintestinal muscles and the propulsion and movement of the lumenalcontents) is controlled by nerves and hormones, as well as by electricalactivity in the muscular wall of the intestine. There are severaldisorders that involve abnormal motility and result in abnormal anduncomfortable visceral sensations. These disorders can cause significantdiscomfort and distress in the absence of gross physical abnormality ofthe intestine.

[0005] For example, irritable bowel syndrome (IBS) is a common disorderof the intestines. IBS can lead to crampy pain, gassiness, bloating, andchanges in bowel habits. Some people with IBS have constipation(difficult or infrequent bowel movements); others have diarrhea(frequent loose stools, often with an urgent need to move the bowels);and some people experience both symptoms intermittently. Sometimes theperson with IBS has a crampy urge to move the bowels, but cannot do so.The cause of IBS is not known, and as yet there is no cure. IBS can becharacterized as a functional disorder because there is no sign ofdisease when the intestine is examined. Often IBS is just a mildannoyance, but for some people it can be disabling.

[0006] Dyspepsia is another example. Dyspepsia is literally translatedas “bad digestion” and is commonly known as indigestion. Motility-likedyspepsia causes persistent or recurring abdominal pain that is centeredin the upper abdomen. People with motilityassociated dyspepsia also mayexperience bloating, nausea, burping and a feeling of fullness thatoccurs soon after eating. It is an extremely common symptom complex,affecting as much as one-fourth of the United States adult population.

[0007] There are other disorders affecting the gastrointestinal tractthat are characterized by abnormal tissue conditions not associated withneural abnormalities.

SUMMARY OF THE INVENTION

[0008] The invention provides systems and methods that treat disordersof the gastrointestinal tract by applying one or more treatment agentsto tissue at or near the region where abnormal neurological symptomsand/or abnormal tissue conditions exist. The treatment agent is selectedto either disrupt abnormal nerve pathways, e.g., associated withdysmotility and/or discomfort, and/or to alleviate abnormal tissueconditions, e.g., to stiffen tissue in order to alleviate disease.

[0009] One aspect of the invention provides systems and methods thatapply a selected treatment agent into contact with tissue at or in aregion of the gastrointestinal tract where dysmotility and/or abnormalvisceral sensations exist. The application of the treatment agent canprovide relief from the pain and symptoms of nerve-relatedgastrointestinal disorders, such as irritable bowel syndrome ormotility-like dyspepsia. Application of the treatment agent may alsoattenuate the dysmotility and alleviate the dysfunction itself. Thesystems and methods may be used as either a primary treatment modality,or may be applied before, during, or after some other primaryintervention.

[0010] According to this aspect of the invention, the treatment agentincludes at least one vanilloid compound. Presence of the vanilloidcompound evokes a desired tissue response, which includes at least oneof the following, e.g., the interruption of nerve impulses which leadsto a reduction of the symptoms that are associated with abnormal nerveimpulses, the diminution of pain impulses, the attenuation of thedysmotility, and/or the alleviation the disease state itself. Thevanilloid treatment agent may be applied to surface tissue, or,alternatively, it may be injected into subsurface tissue. In oneembodiment, the systems and methods can also apply energy to the tissueregion to form at least one lesion in conjunction with application ofthe treatment agent.

[0011] Another aspect of the invention provides systems and methods thatapply a selected treatment agent into contact with tissue at or in aregion where an abnormal tissue condition exists in order to affectnormal functionality.

[0012] According to this aspect of the invention, the treatment agentincludes at least one sub-type of a cytokine. Presence of the cytokineevokes a desired tissue response, which can include, e.g., an initiationof a localized healing process including influx of white blood cells andfibroblasts, followed by deposition of collagen, and subsequent tissuecompliance reduction and tightening. These effects will result in areduction of tissue volume. The cytokine treatment agent may be appliedto surface tissue, or, alternatively, it may be injected into subsurfacetissue, including the submucosa.

[0013] Features and advantages of the inventions are set forth in thefollowing Description and Drawings, as well as in the appended Claims.

BRIEF DESCRIPTION OF THE DRAWINGS

[0014]FIGS. 1A and 1B are schematic views of a system for treatingtissue that includes a treatment device with a tissue piercing memberthat embodies features of the invention, FIG. 1A showing the treatmentdevice deployed in a tissue region and FIG. 1B showing the treatmentdevice piercing the tissue region to inject a treatment agent;

[0015]FIGS. 2A and 2B are schematic views of a system for treatingtissue that includes a treatment device with multiple tissue piercingmembers that embodies features of the invention, FIG. 2A showing thetreatment device deployed in a tissue region and FIG. 2B showing thetreatment device piercing the tissue region to inject a treatment agent;

[0016]FIG. 3 is an embodiment of a tissue treatment device that takesthe form of a syringe and a needle for injecting a treatment agent intoa tissue region that can be visualized from outside the body; and

[0017]FIG. 4 is an embodiment of a tissue treatment device for injectinga treatment agent into a tissue region that cannot be visualized fromoutside the body.

[0018] The invention may be embodied in several forms without departingfrom its spirit or essential characteristics. The scope of the inventionis defined in the appended claims, rather than in the specificdescription preceding them. All embodiments that fall within the meaningand range of equivalency of the claims are therefore intended to beembraced by the claims.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0019] This Specification discloses various systems and methods fortreating dysfunctions of organs or tissue in the gastrointestinal tract.Still, it should be appreciated that the disclosed systems and methodsare applicable for use in treating other dysfunctions elsewhere in thebody, e.g., for treating sphincter barrier dysfunctions in the lowergastrointestinal tract or in the upper gastrointestinal tract. Thesystems and methods that embody features of the invention are adaptablefor use with catheter-based systems and surgical techniques, as well assystems and surgical techniques that are not necessarily catheter-based.

[0020] I. System Overview

[0021] A tissue treatment system 10 that embodies features of theinvention is shown in FIGS. 1A and 1B. The tissue treatment system 10includes a tissue treatment device 12 and an apparatus 14 to deliver thetissue treatment device 12 to a tissue region 16 targeted for treatment.The treatment system 10 also includes a source 18 of a treatment agent20.

[0022] A. The Tissue Treatment Device

[0023] The tissue treatment device 12 serves to apply the treatmentagent 20 to the targeted tissue region 16 to obtain a desiredtherapeutic effect. The therapeutic effect can comprise eitheralteration of nerve impulse pathways in the region 16 or a physicalalteration of tissue characteristics in the region 16.

[0024] The tissue treatment device 12 includes one or more agentdelivery ports 22. The one or more delivery ports 22 can apply thetreatment agent 20 to surface tissue in the region 16. Desirably (asFIG. 1A shows), the port 20 is located at the end of a tissue piercingmember 24. In this arrangement, the treatment agent 20 may be injectedinto subsurface tissue.

[0025] The tissue treatment device 12 can include single or multipleports 22 located single or multiple tissue piercing members 24 to injectthe treatment agent 20. As FIGS. 1A and 1B show, a single tissuepiercing member 24 (with a single port 22) may be used. Alternatively,as FIGS. 2A and 2B show, the treatment device 24 can carry multipletissue piercing members 24, each with a port 22. Desirably, the multipletissue piercing members 24 are arranged in a spaced-apart array, toapply the treatment agent 20 in a prescribed pattern at the targetedsite.

[0026] Alternatively, the tissue treatment device 12 may employ airpowered, needle-less injection technology.

[0027] B. The Delivery Device

[0028] The configuration of the delivery apparatus 14 for the device 12can also vary, depending upon the accessibility of the treatment siteand the particular treatment objectives desired.

[0029] If the treatment site can be directly visualized the deliveryapparatus 14, the source 18, and the treatment device 12 can comprise asyringe 100 and a needle 102, as FIG. 3 shows.

[0030] If the treatment site can not be directly visualized or isotherwise not as readily accessible, the delivery apparatus 14 cancomprise an endoscope 106 having an interior lumen 104 passed down theesophagus through the mouth, as FIG. 4 shows. In this arrangement, thetreatment device 12 is desirably carried on the distal end of a cathetertube 108 for passage through the endoscope lumen 104 to the targetedsite. A guidewire may be used, if desired, to further facilitatedeployment of the endoscope and treatment device to the targeted site.

[0031] C. The Tissue Treatment Agent

[0032] The treatment agent 20 is selected from a group of candidateagents based upon the physiologic effect or effects that are desired.One or more candidate agents may be applied, either as a primarytreatment modality, a neoadjuvent treatment modality, or an adjuventtreatment modality.

[0033] In the illustrated embodiment, the group consists essentially oftwo candidate agents: (1) Vanilloid Compounds, and (2) CytokineSub-Types.

[0034] 1. Vanilloid Compounds

[0035] The treatment agent 20 can comprise a vanilloid compound.Vanilloid compounds have a unique capacity to bind to a membranereceptor in sensory neurons. Capsaicin is one of many vanilloidcompounds. Capsaicin is a powerful basic compound which is derived fromchili peppers.

[0036] The specific neuron for capsaicin is deemed “VR1”. This receptoris expressed only on small unmyelinated C-fibers (nerves typicallyinvolved in special visceral sensation and pain).

[0037] Exposure to vanilloid compounds variably reduces theresponsiveness of the neuron to stimuli. In many cases, the neuron mayactually degenerate either temporarily or permanently, thus impairingtransmission of pain signals or other special sensory signals.

[0038] The term “vanilloid compound” as used herein means a compound ora mixture of compounds having a biologically active vanillyl group.Vanilloid compounds include both naturally occurring vanilloids,synthetic vanilloids, pharmaceutically acceptable salts of the vanilloidcompound (whether natural or synthetic) as well as pharmaceuticallyacceptable derivatives and/or analogues thereof (whether natural orsynthetic). Examples of natural vanilloid compounds include both thecrude extracts and the purified extracts of active vanilloid compoundsfrom: capsicum, cayenne pepper, black pepper, paprika, cinnamon, clove,mace, mustard, ginger, turmeric, papaya seed and the cactus-like plantEuphorbia resinifera.

[0039] Synthetic vanilloid compounds such as synthetic capsaicin aredisclosed in WO 96/40079, which is incorporated herein by reference. Thevanilloid compound family includes: Capsaicin; Dihydrocapsaicin:Nordihydrocapsaicin; Homocapsaicin: Homodihydrocapsaicin. Alternatively,resiniferotoxin (RTX) is derived from the euphorbia cactus and isconsidered a capsaicin-like compound. This substance also activates theVR1 receptor and attenuates or eliminates afferent nerve function,although it may not illicit the rapid heat sensation that othervanilloids produce.

[0040] Other examples of vanilloid compounds include capsaicin((E)-(N)-[(4-hydroxy-3-methoxyphenyl)-methyl]-8-me thyl-6-nonenamide);eugenol (2-methoxy-4-(2-propenyl)phenol); zingerone(4-(4-hydroxy-3-methoxyphenyl)-2-butanone); curcumin(1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione); piperine(1-[5-(1,3-benzodioxol-5-yl)-1-oxo-2,4-pentadienyl] piperidine);resiniferatoxin(6,7-deepoxy-6,7-didehydro-5-deoxy-21-dephenyl-21-(phenylmethyl)-20-(4-hydroxy-3-thoxybenzeneacetate))or pharmaceutically effective salts, analogues, derivatives orequivalents thereof.

[0041] The treatment agent 20 can include capsaicin, another vanilloidcompound, RTX, or combination thereof, alone or in combination withother substances (which will be generically called avanilloid-containing treatment agent 20).

[0042] The vanilloid-containing treatment agent can be applied throughthe port 22 or ports 22 to the mucosal lining or extrinsically to theoutside of an organ. The vanilloid-containing treatment agent can alsobe injected into the targeted tissue region or organ wall.

[0043] The treatment agent 20 can be a solution, a gel, a powder, apellet, or other form. The treatment agent may be released immediately,or, be a sustained release product such as a slow released implant, slowrelease gel, coated pellet, microsphere, or other form.

[0044] The vanilloid-containing treatment agent 20 may be applied orinjected as primary therapy, or, as a neoadjuvant or adjuvant procedure.For example, RF energy may be used to incite a wound, followed byapplication of the vanilloid-containing treatment agent to facilitateexuberant wound healing.

[0045] In dyspepsia and irritable bowel syndrome, the use of avanilloid-containing treatment agent can serve to diminish the painimpulses or could attenuate the dysmotility and alleviate the diseasestate.

[0046] An example of vanilloid materials that can be used is produced byAfferon and is called RTX, which has been instilled into the lumen ofthe urinary bladder for the treatment of urge incontinence. There arealso several topical, over-the-counter capsaicin products for topicalanalgesic applications.

[0047] 2. Cytokine Sub-Types

[0048] The treatment agent 20 can include one or more subtypes ofcytokines. A cytokine, in the natural state within the body, is aprotein produced and released by a biological cell that has an effect onthe local environment surrounding the cell. Cytokines are involved inmany cellular processes, such as wound healing. The mechanism of actionwould depend on the specific cytokine utilized.

[0049] The term “cytokine subtype” as used herein means any polypeptidethat affects the functions of other cells, and is a molecule whichmodulates interactions between cells in the immune or inflammatoryresponse. A cytokine subtype includes, but is not limited to monokinesand lymphokines regardless of which cells produce them. For instance, amonokine is generally referred to as being produced and secreted by amononuclear cell, such as a macrophage and/or monocyte but many othercells produce monokines, such as natural killer cells, fibroblasts,basophils, neutrophils, endothelial cells, brain astrocytes, bone marrowstromal cells, epideral keratinocytes, and B-lymphocytes. Lymphokinesare generally referred to as being produced by lymphocyte cells.Examples of cytokine subtypes include, but are not limited to,interleukin-1 (IL-1), tumor necrosis factor-alpha (TNF alpha) and tumornecrosis factor beta (TNF beta).

[0050] Other cytokine subtypes include TGF-β (transforming growth factorβ); PDGF (platelet derived growth factor); b-FGF (basic fibroblastgrowth factor): IGF-1 (insulin-like growth factor 1); EGF (epidermalgrowth factor); and VEGF. Some of these cytokines are availablecommercially, could be produced commercially, or can be extracted from apersons harvested platelets (platelet releasates). The effects of agiven cytokine upon tissue physiology can include one or more of thefollowing: smooth muscle and fibroblast mitogenic effects (inducesdivision and growth of cells); stimulation of the release of cytokinesfrom other cells; chemoattractant (bringing new healing cells into localregion); decrease of collagen enzyme activity allowing collagen to buildup; inflammation; and angiogenesis (development of new blood vessels).

[0051] The treatment agent 20 can include a cytokine sub-type orcombination of cytokine sub-types, alone or in combination with othersubstances. The cytokine-containing treatment agent can be applied bythe port or ports 22 to the tissue or organ wall, or injected into thetissue or organ wall.

[0052] The cytokine-containing treatment agent 20 can be a solution, agel, a powder, a pellet, or other form. The treatment agent may bereleased immediately, or, be a sustained release product such as a slowreleased implant, slow release gel, coated pellet, microsphere, or otherform.

[0053] The cytokine-containing agent 20 may be applied or injected asprimary therapy, or, as a neoadjuvant or adjuvant procedure. Forexample, radio frequency (RF) energy may be used to induce the woundhealing process, followed by cytokine application to facilitate moreexuberant wound healing.

[0054] The application of a single cytokine or mixture thereof, asprimary, neoadjuvant, or adjuvant therapy for abnormal tissue conditions(e.g., excess tissue volume) could have the various mechanical andtherapeutic effects. With or without an inciting wound event (such asRF), cytokines can serve to initiate the process of healing within thelocal region. This process includes, but is not limited to, influx ofwhite blood cells and macrophages, stimulation of fibroblast and smoothmuscle division and collagen secretion, new blood vessel growth, woundcontraction and tightening, maturation of the new or existing collagenframework, and reduced tissue compliance. These tissue effects couldimprove the compliance and reduce the tissue volume.

[0055] Examples of cytokine materials that can be used includecommercially available Regranex, which is recombinant human PDGF-BB.This material has been applied as a gel for promoting the healing ofdiabetic foot ulcers. Platelet granules contain many of the cytokineslisted above, and the cytokines can be extracted with a fairly simpletechnique (platelet releasates). Platelets (harvested as a pooledplatelet product or from autologous donation) provide a source ofcytokines for extraction. TGF-β and PDGF are considered to be the mostimportant substances for the purpose of initiating the wound healingprocess.

[0056] Various features of the invention are set forth in the followingclaims.

We claim
 1. An apparatus for treating a tissue region where dysmotilityand/or abnormal visceral sensations exist comprising an operativeelement adapted, in use, to be deployed adjacent to the tissue region, asource of treatment agent including at least one vanilloid compoundcoupled to the operative element to apply the treatment agent intocontact with the tissue region.
 2. An apparatus for treating a tissueregion where excess tissue volume exists comprising an operative elementadapted, in use, to be deployed adjacent the tissue region, a source oftreatment agent including at least one cytokine subtype coupled to theoperative element to apply the treatment agent into contact with thetissue region.
 3. An apparatus according to claim 1 or 2 wherein theoperative element applies the treatment agent to surface tissue.
 4. Anapparatus according to claim 1 or 2 wherein the operative elementinjects the treatment agent into subsurface tissue.
 5. An apparatusaccording to claim 1 or 2 further including an electrode to apply energyto the tissue region to form at least one lesion.
 6. An apparatusaccording to claim 5 wherein the treatment agent is applied through alumen in the electrode.
 7. An apparatus according to claim 5 wherein theoperative element applies the treatment agent through a lumen that isadjacent to the electrode.
 8. A method for treating a tissue regionwhere dysmotility and/or abnormal visceral sensations exist comprisingthe steps of deploying an operative element adjacent the tissue region,and applying through the operative element a treatment agent includingat least one vanilloid compound into contact with the tissue region. 9.A method for treating a tissue region where excess tissue volume existscomprising the steps of deploying an operative element adjacent thetissue region, and applying through the operative element a treatmentagent including at least one cytokine subtype into contact with thetissue region.
 10. A method according to claim 8 or 9 further includingthe step of forming at least one lesion in the tissue region to whichthe treatment agent is applied.
 11. A method according to claim 8 or 9wherein the treatment agent is applied to surface tissue.
 12. A methodaccording to claim 8 or 9 wherein the treatment agent is injected intosubsurface tissue.